Throughout this application various publications are referenced by numbers within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Pneumocystis carinii pneumonia (PCP) is the most common life-threatening opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). There is no safe and effective prophylaxis for this infection in patients with AIDS. Prevention of PCP would mean a reduction in mortality, morbidity, and medical costs. Treatment of the infection is costly, facilities for its diagnosis and treatment are scarce, and the number of people at risk is increasing.
Pneumonia due to Pneumocystis carinii occurs in patients with AIDS and in cancer and organ transplant patients. The infection has also been seen in epidemics among premature and malnourished infants. The report in 1981 of PCP in otherwise healthy male homosexuals signaled the emergence of the AIDS epidemic (1). More than 65% of AIDS patients develop PCP (2). In many cases the development of PCP is the first sign of immune dysfunction and thus provides the basis for the diagnosis of AIDS.
Trimethoprim-sulfamethoxazole (SXT) is effective in the prevention and treatment of PCP in experimental animals and in humans. Prophylaxis with SXT has markedly decreased the incidence of PCP among patients with leukemia or lymphoma. Unfortunately, 60-70% of patients with AIDS have adverse reactions to SXT (3). These patients cannot receive SXT prophylaxis and, if they develop PCP, must receive pentamidine.
Pentamidine was the first effective treatment for PCP. It is highly effective in treatment of PCP infection in patients with AIDS. The drug is presently administered by IV infusion or IM injection at 4 mg/kg/day for 14-21 days. Unfortunately, treatment often causes severe toxic reactions including hypotension, renal failure, and hypoglycemia (4). Response to therapy is slow and patients require prolonged hospitalization and intensive, supportive care.
Pentamidine isethionate is an effective form of pentamidine. Pentamidine isethionate has a molecular weight of 592.68 and has the following structure: ##STR1##
Pentamidine is also sold as the naphthoate. Both forms are sold as antiprotozals.
There are currently no methods available for prevention of PCP which have been proven to be safe and effective among patients with AIDS. Several methods are being investigated in clinical trials: these include sulfamethoxazole-trimethoprim (bactrim), sulfadoxinepyrimethamine (fansidar), dapsone, or monthly iv pentamidine. Aerosol pentamidine appears to offer significant advantages over these methods. Because the drug is applied topically there is efficient delivery to the target organ and little systemic absorption. This limits toxicity and provides increased effectiveness.
Pentamidine is effective in the chemoprophylaxis of African trypanosomiasis (sleeping sickness) (7). Human volunteers, subjected weekly to bites from infected tse-tse flies, resisted infection for one year or more after a single IM dose of pentamidine (8). Twice-yearly IV or IM doses eliminated the infection in endemic areas in subsaharn Africa. The drug has been administered to more than ten million people in campaigns to eradicate sleeping sickness. However, no adequate studies of prevention of PCP in humans with IV or IM pentamidine have been reported. In fact, prophylaxis with IV or IM pentamidine was unsuccessful in the animal model of PCP (9).
The route of administration of pentamidine profoundly affects its tissue distribution. After IV or IM administration pentamidine is eliminated rapidly from blood, it accumulates in tissues, and is eliminated slowly from them. The amount of pentamidine that accumulated in the lungs of rats or humans that received IV or IM pentamidine was a small fraction of the amounts that accumulated in other visceral organs. An earlier study showed that aerosol administeration of pentamidine favor its distribution to the lung. However, the relationship between tissue levels and dosage was not determined (10).
The aerosol route delivers pentamidine to the target organ while limiting potentially-toxic accumulation in other organs. The drug is retained in the lungs for many weeks after a single aerosol dose; the half-life of elimination from the lungs in rats was 36 days. Low and infrequent treatment with aerosol pentamidine was highly effective in prevention of PCP in the animal model. No toxicity was seen in histopathologic sections from the lungs of rats that received aerosol pentamidine at doses that greatly exceeded the therapeutic dose (5).
A previous article discloses a new Bioassay for studying pentamidine pharmacokinetics (5). In this article the authors speculate that a better understanding of the pharmacokinetics of pentaimidine should lead to safer, more effective use of the drug in the treatment or prevention of PCP. Elsewhere in the paper, the authors note that aerosol administration also deserves further study. However, there is no disclosure that administration of pentamidine in aerosol form to subjects suseptible to infection by Pneumocystis carinii, particularly effective in preventing Pneumocystic carinii infection and the PCP caused thereby.
An abstract disclosing the use of pentamidine in an aerosol for prevention of PCP was distributed on Mar. 26, 1986 to attendees at the Annual Meeting of the American Society for Microbiology, Washington, D.C.